Oxindole antiinflammatory agents

ABSTRACT

Ketone containing 1-substituted oxindole-3-carboxamides as antiinflammatory agents prepared by reaction of the 1-substituted oxindole with an isocyanate or by aminolysis of the corresponding alkyl oxindole-3-carboxylate.

BACKGROUND OF THE INVENTION

Rheumatoid arthritis, which affects 3-4% of the population, ischaracterized by inflammation and pain of joints. Although the etiologyof rheumatoid arthritis is not known, both steroid and non-steroidaltherapy have been employed to alleviate the symptoms of this illness. Itis to this latter class of chemotherapeutic agents that the compounds ofthe present invention relate.

The potent non-steroidal antiinflammatory agent, Piroxicam,4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide1,1-dioxide was reported in U.S. Pat. No. 3,591,584. More recently,antiinflammatory activity was found in simple non-steroidaloxindole-3-carboxamides, U.S. Pat. No. 3,634,453.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now been found that agroup of novel oxindole carboxamide derivatives are useful asantiinflammatory agents.

The first group of compounds in this series are of the formula: ##STR1##and a pharmaceutically acceptable salt thereof, wherein R₁ is phenyl oralkyl of one to three carbon atoms; Z is oxygen or methylene; and R₂ isphenyl, fluorophenyl, difluorophenyl, pyridyl, trifluoromethylphenyl,nitrophenyl, 2-thiazolyl or 5-methyl-2-thiazolyl.

Preferred in this series of compounds are those where R₁ is alkyl asdefined and Z is methylene. Especially preferred are those compoundswhere R₁ is ethyl and R₂ is 4-fluorophenyl, 2,4-difluorophenyl or3-trifluoromethylphenyl.

The second group of compounds of the present invention are of theformula: ##STR2## and a pharmaceutically acceptable salt thereof,wherein R₁ is phenyl or alkyl of one to three carbon atoms; and R₃ isphenyl, fluorophenyl, difluorophenyl, pyridyl, 2-thiazolyl or5-methyl-2-thiazolyl.

Preferred within this group are compounds wherein R₁ is alkyl asdefined. Especially preferred is the compound wherein R₃ is2,4-difluorophenyl and R₁ is ethyl.

The third group of compounds of the present invention are of the formula##STR3## and a pharmaceutically acceptable salt thereof, wherein R₃ isphenyl, fluorophenyl, difluorophenyl, pyridyl, 2-thiazolyl or5-methyl-2-thiazolyl; R₄ is a substituent at the 5, 6 or 7-position ofthe oxindole selected from acetyl, benzoyl or 2-thenoyl; and R₅ ishydrogen or alkyl having one to three carbon atoms.

Preferred in this group of compounds are those wherein R₅ is alkyl asdefined and R₄ is benzoyl. Especially preferred are the compoundswherein R₅ is ethyl, R₄ is benzoyl at the 5-position of the oxindole andR₃ is 4-fluorophenyl or 5-methyl-2-thiazolyl. Also especially preferredis the compound wherein R₅ is methyl, R₃ is 4-fluorophenyl and R₄ isbenzoyl at the 5-position of the oxindole.

A second preferred group of compounds are those wherein R₅ is hydrogenand R₄ is benzoyl. Especially preferred is the compound wherein R₄ isbenzoyl at the 5-position of the oxindole and R₃ is 2,4-difluorophenyl.

A third preferred group of compounds are those wherein R₅ is alkyl asdefined and R₄ is 2-thenoyl. Especially preferred are the compoundswherein R₅ is ethyl, R₄ is 2-thenoyl at the 5-position of the oxindoleand R₃ is 4-fluorophenyl or 2,4-difluorophenyl.

A fourth preferred group of compounds are those wherein R₅ is alkyl asdefined and R₄ is acetyl. Especially preferred is the compound whereinR₅ is ethyl, R₄ is acetyl at the 5-position of the oxindole and R₃ is2,4-difluorophenyl.

Also part of the present invention is a method of treating aninflammatory disease in a mammalian subject, which comprisesadministering to said mammalian subject an inflammatory disease treatingamount of a compound selected from one or more of the compounds of thepresent invention.

Also contemplated is a pharmaceutical composition, which comprises apharmaceutically-acceptable carrier and a compound of the presentinvention and wherein the weight-ratio of thepharmaceutically-acceptable carrier to said compound is in the ratio offrom 1:4 to 20:1.

DETAILED DESCRIPTION

One of the processes employed in the preparation of the novel compoundsof this invention consists of the interaction of an appropriate oxindolederivative with a requisite isocyanate as follows: ##STR4## wherein R₁and R₅ are as defined and Ar represents R₂ and R₃ as defined.

This reaction leading to the products of the instant invention iscarried out in a reaction-inert solvent. Preferred solvents are polar,aprotic solvents such as dimethylformamide, diethylformamide,N-methyl-2-pyrrolidone or dimethylsulfoxide. Further it is preferredthat the reaction be carried out in the presence of a base. Such basesinclude alkali and alkaline earth metal hydrides or a tertiary organicamine. The preferred base is sodium hydride.

In practice, the isocyanate is added to the oxindole derivative and basein the appropriate solvent. It is preferable to employ about a molarequivalent of the isocyanate and base, with best results achieved byusing an excess of as much as 50% of each. It is preferred that thereagents be combined in the cold, generally from -10° to 0° C., and thatthe reaction mixture be allowed to warm to room temperature. At fromroom temperature to 45° C. the reaction proceeds to completion in abouta few minutes to overnight depending on the reactivity of theisocyanate.

Upon completion of the reaction, the product is isolated by adding themixture to ice-water and treating with sufficient acid to provide a pHof between 2 and 5. The product can be filtered or extracted with awater immiscible solvent.

Purification can be by chromatography or by recrystallization from anappropriate solvent.

A second reaction leading to the novel products of the present inventionconsists of the interaction of an appropriate amine with an oxindoleester 4 as follows: ##STR5## wherein R₁ and R₅ are as defined, R isalkyl of one to four carbon atoms and Ar is as defined.

This reaction leading to the products of the present invention is alsocarried out in a reaction-inert solvent. Preferred solvents are aproticaromatic solvents such as benzene, toluene or xylene.

In practice, the reagents are combined in the appropriate solvent andheated to the reflux temperature of the solvent. It is preferable, inconducting this aminolysis reaction, to employ at least equimoles ofester and amine, although an excess of the amine, such as twoequivalents, is especially preferred. To assist in removal of thealcohol by-product formed in the reaction a soxhlet containing molecularsieves is fitted to the reaction condenser. Using reflux temperatures ofthe solvents the reaction is generally complete in 45-60 minutes.

The product can be isolated by cooling the reaction mixture andfiltering the product or by adding the reaction mixture to an acidifiedaqueous solution followed by extraction of the product and removal ofthe solvent.

Purification can be carried out by recrystallization or chromatography.

The oxindole starting reagents for these processes are prepared by theherein described procedures. The requisite isocyanates are eithercommercially available or can be prepared by standard procedures knownin the art, for instance, Zook and Wagner, Synthetic Organic Chemistry,John Wiley and Sons, Inc., New York, 1956, page 640.

In preparing the oxindole ester intermediate 4, wherein R₄ is acetyl atthe 5- or 6-position it is preferred that the carbonyl of the acetylmoiety be protected by ketal formation in order to minimize interactionof the dialkyl carbonate with the methyl group of the acetyl. The ketalgroup can be hydrolyzed after the oxindole ester has been reacted withthe appropriate amine.

It is noted that a common characteristic of many non-steroidalantiinflammatory agents is their acidic nature. Each of the oxindolecarboxamides of the instant invention shares this property and is aneffective proton source.

Pharmaceutically acceptable salts of the compounds of the presentinvention are also therapeutic agents, wherein the preferred cations ofsaid salts include the ammonium, sodium and potassium ions. Thepharmaceutically acceptable salts of the compounds described herein areprepared by conventional procedures, as for example, by adding the acidto an aqueous solution containing an equivalent amount of thepharmaceutically acceptable base, i.e., a base containing one of theabove preferred cations, followed by concentration of the resultantmixture to obtain the desired product. The bases can be selected fromhydroxides, oxides or carbonates.

Also considered part of the present invention are prodrugs of the hereindescribed compounds. These prodrugs, which have fewer gastrointestinalside effects, breakdown in situ to the parent compound.

As previously indicated, the oxindole carboxamides of the presentinvention and their pharmaceutically acceptable salts are usefulantiinflammatory agents. These compounds are of value in alleviatingswelling and inflammation which are symptomatic of rheumatoid arthritisand related disorders which are responsive to treatment withantiinflammatory agents. Either as individual therapeutic agents or asmixtures of therapeutic agents, they may be administered alone, but aregenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice. For example, they may be administered orally in the form oftablets or capsules containing such excipients as starch, milk sugar orcertain types of clay, etc. They may be administered orally in the formof elixirs or oral suspensions with the active ingredients combined withemulsifying and/or suspending agents. They may be injected parenterally,and for this use they, or appropriate derivatives, may be prepared inthe form of sterile aqueous solutions. Such aqueous solutions should besuitably buffered, if necessary, and should contain other solutes suchas saline or glucose to render them isotonic. The weight-ratio of thepharmaceutically-acceptable carrier to compound can be from 1:4 to 20:1.

The dosage required to reduce inflammation or swelling in arthriticsubjects would be determined by the nature and extent of the symptoms.Generally, small doses will be required initially, with a gradualincrease in the dose until the optimum level is determined. It willgenerally be found that when the composition is administered orally,larger amounts of the active ingredient will be required to produce thesame level as produced by a smaller quantity administered parenterally.In general, from about 10 to about 300 mg. of active ingredient perkilogram of body weight, administered orally in single or multiple doseunits, will effectively reduce inflammation and swelling. Parenteraladministration requires doses of from about 5 to about 200 mg of activeingredient to achieve the same end point.

A standard procedure for detecting and comparing antiinflammatoryactivity of compounds is the carrageenin rat foot edema test, which isdescribed by C. A. Winter et al., Proc. Soc. Exp. Biol., vol III, page544 (1962).

In addition to being useful as antiinflammatory agents, the compounds ofthe present invention can be used in the treatment of asthma, bronchitisand psoriasis; they can also be used as analgesic agents.

The following examples are provided solely for the purpose of furtherillustration. Nuclear magnetic resonance spectra (NMR) were measured at60 MHz for solutions in deuterochloroform (CDCl₃), perdeutero dimethylsulfoxide (DMSO-d₆) or deuterium oxide (D₂ O) or are noted otherwise,and peak positions are expressed in parts per million (ppm) downfieldfrom tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate.The following abbreviations for peak shapes are used: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet; b, broad.

EXAMPLE 1N-(2,4-Difluorophenyl)-1-ethyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole-3-carboxamide(1, R₁ =C₂ H₅, R₂ =2,4-difluorophenyl, Z=CH₂)

To 103.5 mg. (4.5 mmoles) of sodium hydride in 4.5 ml. ofdimethylformamide was added 645 mg. (3 mmoles) of1-ethyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole followedafter 20 minutes by 698 mg. (4.5 mmoles) of 2,4-difluoroisocyanate.After stirring for 30 minutes the reaction mixture was poured into amixture of 2N hydrochloric acid and methylene chloride. The organicphase was separated, dried over sodium sulfate and concentrated todryness. The residue was recrystallized from diisopropyl ether-methylenechloride, 872 mg. (79% yield), m.p. 190°-197° C. (dec.).

Anal. Calcd. for C₂₀ H₁₆ O₃ N₂ F₂ : C, 64.9; H, 4.4; N, 7.6. Found: C,64.7; H, 4.3; N, 7.7.

EXAMPLE 2

Employing the procedure of Example 1, and starting with the appropriateregents, the following compounds were prepared:

    ______________________________________                                         ##STR6##                                                                                              m.p.                                                 R.sub.1                                                                            R.sub.2      Z      °C.                                                                         NMR(CDCl.sub.3)ppm.                             ______________________________________                                        C.sub.2 H.sub.5                                                                     ##STR7##    CH.sub.2                                                                             130- 135                                                                           1.29 (t, J=7Hz, CH.sub.3), 2.7 (CH.sub.2),                                    3.15 (CH.sub.2), 3.9 (q, J=7Hz, NCH.sub.2),                                   4.4 (s, CH), 6.9-7.7 (ArH), 7.91 (ArH) and                                    9.6 (NH).                                       C.sub.2 H.sub.5                                                                     ##STR8##    CH.sub.2                                                                             180- 188                                                                           1.31 (t, J=7Hz, CH.sub.3), 2.75 (CH.sub.2),                                   3.15 (CH.sub.2), 3.92 (q, J=7Hz,                                              NCH.sub.2), 4.43 (s, CH), 7.1-8.0 (ArH) and                                   9.83 (NH).                                      C.sub.2 H.sub.5                                                                     ##STR9##    O      178- 180                                                                           1.31 (t, J=7Hz, CH.sub.3), 3.82 (q, J=7Hz,                                    CH.sub.2), 4.4 (CH), 4.65 (s, OCH.sub.2),                                     6.8-7.6 (ArH), 7.6 (ArH) and 9.63 (NH).         C.sub.2 H.sub.5                                                                     ##STR10##   CH.sub.2                                                                             185- 190                                                                           1.32 (t, J=7Hz, CH.sub.3), 2.75 (CH.sub.2),                                   3.18 (CH.sub.2), 3.92 (d, J=7Hz,                                              NCH.sub.2), 4.42 (s, CH), 6.98 (d, J=8Hz,                                     ArH), 7.2 (ArH), 7.56 (d, J=8Hz, ArH), 7.91                                   (ArH) and 9.63 (NH).                            C.sub.2 H.sub.5                                                                     ##STR11##   CH.sub.2                                                                             168- 175                                                                           1.31 (t, J=7Hz, CH.sub.3), 2.75,                                              (CH.sub.2), 3.17 (CH.sub.2), 3.9 (q, J=7Hz,                                   NCH.sub.2), 4.42 (s, CH), 7.2 (ArH), 7.72                                     (d, J=9Hz, ArH), 7.9 (ArH), 8.16 (d, J=9Hz,                                   ArH) and 10.13 (NH).                            ______________________________________                                    

EXAMPLE 3

Starting with the appropriate reagents and employing the procedure ofExample 1, the following compounds are prepared:

    ______________________________________                                         ##STR12##                                                                    R.sub.1        R.sub.2         Z                                              ______________________________________                                        CH.sub.3                                                                                      ##STR13##      CH.sub.2                                       CH.sub.3                                                                                      ##STR14##      O                                              CH.sub.3                                                                                      ##STR15##      CH.sub.2                                       C.sub.2 H.sub.5                                                                               ##STR16##      CH.sub.2                                        ##STR17##                                                                                    ##STR18##      O                                               ##STR19##                                                                                    ##STR20##      O                                               -n-C.sub.3 H.sub.7                                                                           ##STR21##      CH.sub.2                                        -n-C.sub.3 H.sub.7                                                                           ##STR22##      O                                               .sub.-i-C.sub.3 H.sub.7                                                                      ##STR23##      O                                               .sub.-i-C.sub.3 H.sub.7                                                                      ##STR24##      O                                              ______________________________________                                    

EXAMPLE 4N-(2,4-difluorophenyl)-1-ethyl-2,3,6,11-tetrahydro-2,11-dioxo-[2]benzoxepino[3,4-f]indole-3-carboxamide(2, R₁ =C₂ H₅, R₃ =2,3-difluorophenyl)

To a slurry of 56 mg. (1.4 mmoles) of 60% sodium hydride in 3 ml. ofdimethylformamide was added 293 mg. (1.0 mmole) of1-ethyl-2,3,6,11-tetrahydro-2,11-dioxo[2]benzoxepino[3,4-f]indole. After15 minutes 217 mg. (1.4 mmoles) of 2,4-difluorophenylisocyanate in 0.75ml. of dimethylformamide was added. After stirring for 30 minutes thereaction mixture was added to a mixture of ice water and methylenechloride. The organic phase was separated, dried over magnesium sulfateand concentrated to dryness to give the crude product, which wasrecrystallized from methylene chloride diisopropyl ether, 225 mg. (50%yield), m.p. 193°-199° C.

Anal. Calcd. for C₂₅ H₁₈ F₂ N₂ O₄ : C, 67.0; H, 4.1; N, 6.3. Found: C,66.9; H, 4.4; N, 6.2.

EXAMPLE 5

Starting with the appropriate isocyanate and1-alkayl-2,3,6,11-tetrahydro-2,11-dioxo-[2]benzoxepino[3,4-f]indole andemploying the procedure of Example 4, the following compounds areprepared:

    ______________________________________                                         ##STR25##                                                                    R.sub.1           R.sub.3                                                     ______________________________________                                        CH.sub.3                                                                                         ##STR26##                                                  CH.sub.3                                                                                         ##STR27##                                                  CH.sub.3                                                                                         ##STR28##                                                  CH.sub.3                                                                                         ##STR29##                                                  CH.sub.3                                                                                         ##STR30##                                                  C.sub.2 H.sub.5                                                                                  ##STR31##                                                  C.sub.2 H.sub.5                                                                                  ##STR32##                                                  C.sub.2 H.sub.5                                                                                  ##STR33##                                                  C.sub.2 H.sub.5                                                                                  ##STR34##                                                   -n-C.sub.3 H.sub.7                                                                              ##STR35##                                                   -n-C.sub.3 H.sub.7                                                                              ##STR36##                                                   .sub.-i-C.sub.3 H.sub.7                                                                         ##STR37##                                                  C.sub.2 H.sub.5                                                                                  ##STR38##                                                  ______________________________________                                    

EXAMPLE 6 N-(4-Fluorophenyl)-1-ethyl-5-benzoyloxindole-3-carboxamide (3,R₃ =4-fluorophenyl, R₄ =5-benzoyl, R₅ =ethyl)

A mixture of 1.0 g. (2.96 mmoles) of ethyl5-benzoyloxindole-3-carboxylate and 560 ul. (5.92 mmoles) of4-fluoroaniline in 50 ml. of benzene were heated to reflux through asoxhlet filled with 4A molecular sieves for 45 minutes. The reactionmixture was cooled in ice and added to a mixture of 400 ml. of 2Nhydrochloric acid and 200 ml. of methylene chloride. The organic phasewas separated dried over magnesium sulfate and concentrated to give 1.26g. of crude product, which was recrystallized from diisopropylether-methylene chloride, 611 mg. (51.3% yield), m.p. 125°-128° C.

Anal. Calcd. for C₂₄ H₁₉ O₃ N₂ F: C, 71.6; H, 4.8; N, 7.0. Found: C,71.8; H, 5.0; N, 6.9.

EXAMPLE 7

Starting with the appropriate ethyl benzoyloxindole-3-carboxylate andamine, and employing the procedure of Example 6, the following compoundswere prepared:

    ______________________________________                                         ##STR39##                                                                                  Substitution                                                    R.sub.3       Position   R.sub.5   m.p. °C.                            ______________________________________                                         ##STR40##    5-         C.sub.2 H.sub.5                                                                         187                                        The NMR (d.sub.6 -DMSO) spectrum showed absorption at 1.2                     (t, J = 7Hz, CH.sub.3), 2.3 (s, CH.sub.3), 3.91 (q, J = 7Hz, CH.sub.2)        and                                                                           7.0-8.2 (m, ArH) ppm.                                                          ##STR41##    5-         C.sub.2 H.sub.5                                                                         147-149                                    Anal. Calcd. for C.sub.24 H.sub.18 O.sub.3 N.sub.2 F.sub.2 : C, 68.6; H,      4.3; N, 6.7.-Found: C, 68.6; H, 4.4; N, 6.7.                                   ##STR42##    5-         C.sub.2 H.sub.5                                                                         242-245                                    Anal. Calcd. for C.sub.23 H.sub.19 O.sub.3 N.sub.3 : C, 71.7; H, 5.0; N,      10.9.                                                                         Found: C, 71.7; H, 5.0; N, 10.9.                                               ##STR43##    7-         H         195-200                                    Anal. Calcd. for C.sub.22 H.sub.14 O.sub.3 N.sub.2 F.sub.2 : C, 67.4; H,      3.6; N, 7.1.                                                                  Found: C, 66.9; H, 3.9; N, 7.1.                                                ##STR44##    7-         H         213-217                                    Anal. Calcd. for C.sub.22 H.sub.15 O.sub.3 N.sub.2 F: C, 70.6; H, 4.0; N,     7.5.                                                                          Found: C, 70.3; H, 4.2; N, 7.4.                                                ##STR45##    7-         H         194-195                                    Anal. Calcd. for C.sub.22 H.sub.16 O.sub.3 N.sub.2 : C, 74.2; H, 4.5; N,      7.9.                                                                          Found: C, 74.0; H, 4.6; N, 7.7.                                                ##STR46##    7-         H         258(dec.)                                  ______________________________________                                    

The NMR (D₆ -DMSO) spectrum showed absorption at 2.3 (s, CH₃), 6.92 (bs,NH), 7.62 (bs, ArH) and 8.1 (m, ArH) ppm.

EXAMPLE 8 N-(4-Fluorophenyl)-1-methyl-7-benzoyloxindole-3-carboxamide(3, R₃ =4-fluorophenyl, R₄ =7-benzoyl, R₅ =CH₃)

To a slurry of 191 mg. of sodium hydride in 1.5 ml. of dimethylformamidecooled in an ice bath was added 1.0 g. (3.98 mmoles) of1-methyl-7-benzoyloxindole in 2 ml. of the same solvent. After theevolution of hydrogen gas ceased (15 minutes) 644 ul. (5.97 mmoles) of4-fluorophenylisocyanate was added, and the reaction mixture allowed tostir for 30 minutes. The reaction mixture was then poured into a mixtureof 250 ml. of ice and 2N hydrochloric acid and 100 ml. of methylenechloride. The organic phase was separated, dried over magnesium sulfateand concentrated to give 2.0 g. of a residue, which was chromatographedon 80 g. of silica gel using methylene chloride as the eluent. Thefractions containing the product were combined and concentrated todryness. The residue was recrystallized from diisopropyl ether-methylenechloride, 631 mg. (41% yield), m.p. 173-177.

The NMR (CDCl₃) spectrum showed absorption at 3.09 (s, CH₃), 4.43 (s,CH), 6.8-8.0 (ArH) and 9.53 (s, NH) ppm.

EXAMPLE 9 N-(2,4-Difluorophenyl)-1-ethyl-6-benzoyloxindole-3-carboxamide(3, R₃ =2,4-difluorophenyl, R₄ =6-benzoyl, R₅ =C₂ H₅)

To a slurry of 48 mg. (2 mmoles) of sodium hydride in 2 ml. ofdimethylformamide was added 300 mg. (1.13 mmoles) of1-ethyl-6-benzoyloxindole followed after 20 minutes by the addition of310 mg. (2 mmoles) of 2,4-difluorophenylisocyanate. After stirring for30 minutes the reaction was added to a mixture of 2N hydrochloric acidand methylene chloride. The organic phase was separated, dried overmagnesium sulfate and concentrated to dryness. The residue wasrecrystallized from diisopropyl ether--methylene chloride to give 371mg. (78% yield) of the desired product, m.p. 149°-151° C.

The NMR (CDCl₃) spectrum showed absorption at 1.31 (t, J=7 Hz, CH₃),3.92 (q, J=7 Hz, CH₂), 4.45 (s, CH), 6.6-8.4 (m, ArH) and 9.85 (bs, NH)ppm.

EXAMPLE 10

Employing the procedure of Example 9, and starting with the appropriate6-benzoyloxindole and isocyanate, the following compounds are prepared:

    ______________________________________                                         ##STR47##                                                                    R.sub.3                R.sub.5                                                ______________________________________                                         ##STR48##             H                                                       ##STR49##             H                                                       ##STR50##             CH.sub.3                                                ##STR51##             CH.sub.3                                                ##STR52##             C.sub.2 H.sub.5                                         ##STR53##             C.sub.2 H.sub.5                                         ##STR54##             C.sub.2 H.sub.5                                         ##STR55##              -n-C.sub.3 H.sub.7                                     ##STR56##              -n-C.sub.3 H.sub.7                                     ##STR57##              .sub.-i-C.sub.3 H.sub.7                                ##STR58##              .sub.-i-C.sub.3 H.sub.7                                ##STR59##              .sub.-i-C.sub.3 H.sub.7                                ##STR60##              .sub.-i-C.sub.3 H.sub.7                                ##STR61##             CH.sub.3                                               ______________________________________                                    

EXAMPLE 11N-(2,4-Difluorophenyl)-1-ethyl-5-(2-thenoyl)oxindole-3-carboxamide (3,R₃ =2,4-difluorophenyl, R₄ =5-thenoyl, R₅ =C₂ H₅

A mixture of 1.0 g. (2.91 mmoles) of ethyl1-ethyl-5-(2-thenoyl)oxindole-3-carboxylate and 750 mg. (5.82 mmoles) of2,4-difluoroaniline in 50 ml. of benzene was heated to reflux through asoxhlet filled with 4A molecular sieves for 45 minutes. The reactionmixture was poured into 400 ml. of 2N hydrochloric acid and 200 ml. ofmethylene chloride. The organic phase was separated, dried overmagnesium sulfate and concentrated to dryness in vacuo.Recrystallization of the residue from diisopropyl ether--methylenechloride gave 714 mg. (57.6% yield) of the desired product, m.p.165°-168° C.

The NMR (CDCl₃) spectrum showed absorption at 1.32 (t, J=7 Hz, CH₃),3.87 (q, J=7 Hz, CH₂), 4.5 (s, CH), 6.6-7.3 (m, ArH), 7.6-8.4 (ArH) and9.68 (s, NH) ppm.

EXAMPLE 12

Starting with the appropriate amine and ethyl1-ethyl-5-(2-thenoyl)oxindole-3-carboxylate and employing the procedureof Example 11, the following compounds were prepared:

    ______________________________________                                         ##STR62##                                                                    R.sub.3        m.p., °C.                                                                        NMR, ppm.                                            ______________________________________                                         ##STR63##     198       .sup.a                                                ##STR64##     92-95     .sup.b                                                ##STR65##     235 (dec.)                                                                              .sup.c                                               ______________________________________                                         .sup.a (d.sub.6 -DMSO) 1.2 (t, J=7Hz, CH.sub.3), 2.3 (s, CH.sub.3), 3.89      (q, J=7Hz, CH.sub.2) and 7.0-8.3 (m, ArH).                                    .sup.b (CDCl.sub.3) 1.31 (t, J=7Hz, CH.sub.3), 3.84 (q, J=7Hz, CH.sub.2),     4.41 (s, CH), 6.8-8.4 (m, ArH) and 9.5 (s, NH).                               .sup.c (D.sub.6DMSO + NaOD) 1.19 (t, J=7Hz), 3.93 (q, J=7Hz, CH.sub.2) an     6.7-8.4 (ArH).                                                           

EXAMPLE 13

Using the procedure of Example 11 and starting with the requisite amineand alkyl 1-alkyl-5, 6 or 7-(2-thenoyl)oxindole-3-carboxylate, thefollowing compounds are prepared:

    ______________________________________                                         ##STR66##                                                                                             Substitution                                         R.sub.3          R.sub.5 Position                                             ______________________________________                                         ##STR67##       H       5-                                                    ##STR68##       H       5-                                                    ##STR69##       CH.sub.3                                                                              5-                                                    ##STR70##       C.sub.2 H.sub.5                                                                       6-                                                    ##STR71##       CH.sub.3                                                                              5-                                                    ##STR72##       C.sub.2 H.sub.5                                                                       6-                                                    ##STR73##       H       6-                                                    ##STR74##       C.sub.2 H.sub.5                                                                       6-                                                    ##STR75##       C.sub.2 H.sub.5                                                                       6-                                                    ##STR76##       CH.sub.3                                                                              7-                                                    ##STR77##       C.sub.2 H.sub.5                                                                       7-                                                    ##STR78##       H       7-                                                    ##STR79##         -n-C.sub.3 H.sub.7                                                                  6-                                                    ##STR80##         -n-C.sub.3 H.sub.7                                                                  6-                                                    ##STR81##         -n-C.sub.3 H.sub.7                                                                  7-                                                    ##STR82##         -n-C.sub.3 H.sub.7                                                                  7-                                                    ##STR83##        .sub.-i-C.sub.3 H.sub.7                                                              5-                                                    ##STR84##        .sub.-i-C.sub.3 H.sub.7                                                              7-                                                    ##STR85##        .sub.-i-C.sub.3 H.sub.7                                                              6-                                                   ______________________________________                                    

EXAMPLE 14 N-(2-Pyridyl)-7-acetyloxindole-3-carboxamide (3, R₃=2-pyridyl, R₄ =7-acetyl, R₅ =H)

A mixture of 800 mg. (3.2 mmoles) of ethyl7-acetyloxindole-3-carboxylate and 1.22 g. (12.7 mmoles) of2-aminopyridine in 3.2 ml. of dimethylformamide was heated at 80° C. for24 hours under a nitrogen atmosphere. The reaction mixture was added to100 ml. of 2N hydrochloric acid and the solids filtered, washed withwater and dried, 670 mg. The solids were triturated with methylenechloride, washed with water and dissolved in 50 ml. of water to which 1Nsodium hydroxide solution was added until a solution resulted. Theproduct was precipitated by the addition of 4N hydrochloric acid, andisolated by centrifugation, 219 mg. (23% yield), m.p. 240° C. (dec.).

The NMR (d₆ -DMSO+NaOD) spectrum showed absorption at 2.52 (s, CH₃) and6.6-8.4 (m, ArH) ppm.

EXAMPLE 15 N-(4-Fluorophenyl)-7-acetyloxindole-3-carboxamide (3, R₃=4-fluorophenyl, R₄ =7-acetyl, R₅ =H)

A mixture of 1.0 g. (4.0 mmoles) of ethyl 7-acetyloxindole-3-carboxylateand 1.79 g (16.2 mmoles) of 4-fluoroaniline in 4 ml. ofdimethylformamide was heated to 80° C. under a nitrogen atmosphere forone hour. The reaction mixture was poured into 600 ml. of cold 2Nhydrochloric acid, and the resulting precipitate filtered and dried invacuo, 1.1 g. The crude material was recrystallized from diisopropylether--methylene chloride, 297 mg. (23.5% yield), m.p. 226°-229° C.

The NMR (d₆ -DMSO) spectrum showed absorption at 2.6 (s, CH₃), 7.0-8.0(m, ArH) and 10.5 (bs) ppm.

EXAMPLE 16

Starting with the requisite ethyl 7-acetyloxindole-3-carboxylate and theappropriate amine, and employing the procedure of Example 15, thefollowing compounds are prepared:

    ______________________________________                                         ##STR86##                                                                    R.sub.3               R.sub.5                                                 ______________________________________                                         ##STR87##            H                                                        ##STR88##            H                                                        ##STR89##            H                                                        ##STR90##            H                                                        ##STR91##            H                                                        ##STR92##            CH.sub.3                                                 ##STR93##            CH.sub.3                                                 ##STR94##            CH.sub.3                                                 ##STR95##            C.sub.2 H.sub.5                                          ##STR96##            C.sub.2 H.sub.5                                          ##STR97##            C.sub.2 H.sub.5                                          ##STR98##              -n-C.sub.3 H.sub.7                                     ##STR99##              -n-C.sub.3 H.sub.7                                     ##STR100##            .sub.-i-C.sub.3 H.sub.7                                 ##STR101##            .sub.-i-C.sub.3 H.sub.7                                 ##STR102##            .sub.-i-C.sub.3 H.sub.7                                ______________________________________                                    

EXAMPLE 17 N-(2,4-Difluorophenyl)-1-ethyl-5-acetyloxindole-3-carboxamide(3, R₃ =2,4-difluoro phenyl, R₄ =5-acetyl, R₅ =C₂ H₅) A.N-(2,4-difluorophenyl)-1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxamide

A mixture of 1.0 g. (3.1 mmoles) of ethyl1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylateand 809 mg. (6.3 mmoles) of 2,4-difluoroaniline in 40 ml of benzene washeated to reflux through a soxhlet filled with 4A sieves for 45 minutes.The reaction mixture was cooled and poured into a mixture of 400 ml. 2Nhydrochloric acid and 100 ml. of methylene chloride. The organic layerwas separated, dried over magnesium sulfate and concentrated to give1.24 g. of a solid residue. Recrystallization from diisopropylether--methylene chloride gave 1.0 g. of product (80% yield), m.p.166°-170° C.

Anal. Calcd. for C₂₁ H₂₀ O₄ N₂ F₂ : C, 62.7; H, 5.0; N, 7.0. Found: C,62.6; H, 5.0; N, 7.0.

B. N-(2,4-difluorophenyl)-1-ethyl-5-acetyloxindole-3-carboxamide

N-(2,4-Difluorophenyl)-1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxamide(636 mg., 1.58 mmoles) was dissolved in 15 ml. of tetrahydrofuran towhich was added 10 ml. of 1N hydrochloric acid. The solution was stirredfor one hour followed by the addition of an equal volume of water. Theresulting precipitate was filtered, vacuum dried and recrystallized fromdiisopropyl ether--methylene chloride, 412 mg. (73% yield), m.p.160°-161° C.

Anal. Calcd. for C₁₉ H₁₆ O₃ N₂ F₂ : C, 63.7; H, 4.5; N, 7.8. Found: C,63.5; H, 4.5; N, 7.7.

EXAMPLE 18N-(5-Methylthiazol-2-yl)1-ethyl-5-acetyloxindole-3-carboxamide

Starting with 500 mg. (1.57 mmoles) of ethyl1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylateand 357 mg. (3.1 mmoles) of 2-amino-5-methylthiazole and employing theprocedure of Example 17 gave 342 mg. (63% yield) of the desired product,m.p. 215° C. (dec.).

The NMR (d₆ -DMSO+NaOD) spectrum showed absorption at 1.18 (t, J=7 Hz,CH₃), 2.32 (s, CH₃), 2.56 (s, CH₃), 6.95 (m, ArH), 7.53 (dd, J=8 and 2Hz, ArH) and 8.40 (s, ArH) ppm.

EXAMPLE 19

Starting with the appropriate amine and the requisite ethyl 5 or6-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and usingthe procedure of Example 17, the following compounds are made:

    ______________________________________                                         ##STR103##                                                                                            Substitution                                         R.sub.3          R.sub.5 Position                                             ______________________________________                                         ##STR104##      H       5-                                                    ##STR105##      H       5-                                                    ##STR106##      H       5-                                                    ##STR107##      CH.sub.3                                                                              5-                                                    ##STR108##      CH.sub.3                                                                              5-                                                    ##STR109##      CH.sub.3                                                                              5-                                                    ##STR110##      C.sub.2 H.sub.5                                                                       5-                                                    ##STR111##      C.sub.2 H.sub.5                                                                       5-                                                    ##STR112##        -n-C.sub.3 H.sub. 7                                                                 5-                                                    ##STR113##        -n-C.sub.3 H.sub.7                                                                  5-                                                    ##STR114##       .sub.-i-C.sub.3 H.sub.7                                                              5-                                                    ##STR115##      H       6-                                                    ##STR116##      H       6-                                                    ##STR117##      H       6-                                                    ##STR118##      CH.sub.3                                                                              6-                                                    ##STR119##      CH.sub.3                                                                              6-                                                    ##STR120##      CH.sub.3                                                                              6-                                                    ##STR121##      C.sub.2 H.sub.5                                                                       6-                                                    ##STR122##      C.sub.2 H.sub.5                                                                       6-                                                    ##STR123##        -n-C.sub.3 H.sub.7                                                                  6-                                                    ##STR124##        -n-C.sub.3 H.sub.7                                                                  6-                                                   ______________________________________                                    

PREPARATION A ##STR125##1-Ethyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole A1.1-ethyl-5-formyloxindole

To a solution of 32.2 g. (0.2 mole) of 1-ethyloxindole in 200 ml. ofmethylene chloride was added 44 ml. (0.4 mole) of titanium tetrachloridefollowed by 22.6 ml. (0.25 mole) of dichloromethyl methyl ether. Thereaction was stirred for 10.5 days at 25° C. followed by the addition ofadditional titanium tetrachloride and dichloromethyl methyl ether every48 hours. The reaction was poured onto 1 l. of ice and water andextracted with methylene chloride. Concentration of the dried extractgave the crude product which was recrystallized from diethyl ether, 28.6g. (76% yield), m.p. 126°-127° C.

The NMR (CDCl₃) spectrum showed absorption at 1.28 (t, J=7 Hz, CH₃),3.56 (s, CH₂), 3.79 (q, J=7 Hz, NCH₂), 6.89 (d, J=8.5 Hz, ArH), 7.7 (bs,ArH), 7.74 (bd, ArH) and 9.98 (s, CHO) ppm.

A2. 1-ethyl-5-(trans-carbomethoxyvinylene)oxindole

To a slurry of 1.74 g. (72.7 mmoles) of sodium hydride in 100 ml. oftetrahydrofuran and 50 ml. of dimethylformamide at 0° C. was addedslowly 13.2 g. (72.7 mmoles) of methyl dimethylphosphonoacetate. To theresulting clear solution was added over a 10 minute period 10 g. (52.9mmoles) of 1-ethyl-5-formyloxindole in 50 ml. of tetrahydrofuran and 50ml. of dimethylformamide. The reaction was stirred for 10 minutes andwas then added to 1 l. of ice and water and 400 ml. of diethyl ether.The organic layer was separated and washed with water (1×300 ml.) and asaturated brine solution (1×300 ml.). The aqueous layer was furtherextracted diethyl ether. The extracts were combined, dried andconcentrated to give the crude product. Recrystallization from ethergave 12.9 g. (100% yield) of the titled intermediate.

The NMR (CDCl₃) spectrum showed absorption at 1.28 (t, J=7 Hz, CH₃),3.53 (s, CH₂), 3.79 (q, J=7 Hz, NCH₂), 3.8 (s, OCH₃), 6.35 (d, J=15 Hz,vinyl H), 6.8 (d, J=8 Hz, ArH), 7.4 (m, ArH) and 7.61 (d, J=15 Hz, vinylH) ppm.

A3. 1-ethyl-5-(2-carbomethoxyethyl)oxindole

A mixture of 12.9 g. (52.6 mmoles) of1-ethyl-5-(trans-carbomethoxyvinylene)oxindole and 2.0 g. 5%palladium-on-carbon (50% water) in 400 ml. of methanol was shaken in ahydrogen atmosphere at an initial pressure of 1 atm. After 1 hour thecatalyst was filtered and the filtrate evaporated. The residue wasdissolved in methylene chloride, dried over magensium sulfate and thesolvent evaporated to give 12.9 g. (99% yield) of the desired product.

The NMR (CDCl₃) spectrum showed absorption at 1.24 (t, J=7 Hz, CH₃),2.4-3.2 (m, CH₂), 3.45 (s, CH₂), 3.65 (s, OCH₃), 3.80 (q, J=7 Hz, NCH₂),6.7 (d, J=8 Hz, ArH) and 7.05 (m, ArH) ppm.

A4. 1 ethyl-5-(2-carboxyethyl)oxindole

To a solution of 12.9 g. (52.2 mmoles) of1-ethyl-5-(2-carbomethoxyethyl)oxindole in 53 ml. of methanol was added112.5 ml. of 1N sodium hydroxide solution. After stirring for 1 hour thereaction mixture was acidified by the addition of 165 ml. of 1Nhydrochloric acid. The precipitated product was filtered and dried,11.39 g. (93% yield).

The NMR (CDCl₃) spectrum showed absorption at 1.27 (t, J=7 Hz, CH₃),2.2-3.1 (m, CH₂), 3.48 (s, CH₂), 3.79 (q, J=7 Hz, NCH₂), 6.67 (d, J=8Hz, ArH) and 7.1 (m, ArH) ppm.

A5. 1-ethyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole

To a solution of 6.99 g. (30 mmoles) of1-ethyl-5-(2-carboxyethyl)oxindole in 120 ml. of methylene chloride at25° C. was added 6.86 g. (33 mmoles) of phosphorous pentachloride. Afterstirring 25 minutes the reaction was cooled to -15° C. and 16 g. (0.12mole) of aluminum chloride was added. The mixture was stirred at -15° C.for 1.5 hours and 2.5 hours at 0° C. The mixture was then treated with200 ml. of ice water and 200 ml. of methylene chloride. The organicphase was separated and the aqueous again extracted with the samesolvent (100 ml.). The combined extracts were washed with a saturatedsodium bicarbonate solution (1×200 ml.) and dried over sodium sulfate.The solvent was removed and the residue recrystallized from diethylether to give 5.24 g. (81% yield) of the titled intermediate, m.p. 175°C.

The NMR (CDCl₃) spectrum showed absorption at 1.28 (t, J=7 Hz, CH₃),2.75 (m, CH₂), 3.15 (m, CH₂), 3.59 (s, CH₂), 3.85 (q, J=7 Hz, NCH₂),7.12 (s, ArH) and 7.34 (bs, ArH) ppm.

Starting with the appropriate 1-substituted-5-hydroxyoxindole andfollowing the procedure of Preparation A,1-methyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole,1-phenyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole,1-n-propyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole and1-i-propyl-2,7-dioxo-2,3,5,6-tetrahydro-7H-cyclopenta[f]indole areprepared.

PREPARATION B ##STR126##5-Ethyl-3,6-dioxo-2,3,6,7-tetrahydrofuro[2,3-f]indole B1.1-ethyl-5-chloroacetoxyoxindole

To a slurry of 100 g. (0.565 mole) of 1-ethyl-5-hydroxyoxindole in 91.3ml. (1.13 moles) of pyridine and 565 ml. of dichloromethane at 0° C. wasadded dropwise a solution of 89.3 ml. (1.13 moles) of chloroacetylchloride in 100 ml. of dichloromethane. The reaction mixture was allowedto stir for 15 minutes, and was then added to 1 l. of ice cold 2Nhydrochloric acid and 500 ml. of dichloromethane. The aqueous layer wasextracted once again with 300 ml. of dichloromethane and the combinedorganic extracts washed once with 500 ml. of a saturated brine solution,dried over magnesium sulfate and concentrated to give the desiredproduct in quantitative yield. A small sample was crystallized fromhexane, m.p. 53°-57° C.

The NMR spectrum (CDCl₃) showed absorption at 1.23 (J=7 Hz, CH₃), 3.5(CH₂), 3.72 (J=7 Hz, NCH₂), 4.26 (ClCH₂) and 6.6-7.1 (ArH) ppm.

B2. 5-ethyl-3,6-dioxo-2,3,6,7-tetrahydrofuro[2,3-f]indole

To 142.9 g. (0.565 mole) of 1-ethyl-5-chloroacetoxyoxindole was addedslowly 301 g. (2.26 moles) of aluminum chloride, and the resultingreaction mixture heated to 165° C. for one hour and then allowed to stirfor 15 minutes. The hot reaction mixture was added to 4 l. of ice andwater and the resulting precipitate filtered and dried. The aqueousfiltrate was extracted (6×300 ml.) with dichloromethane, and thecombined extract dried over magnesium sulfate and concentrated todryness. The residue was combined with filtered product andrecrystallized from ethyl acetate, 85.9 g. (70%), m.p. 181°-184° C.

The NMR spectrum (CDCl₃) showed absorption at 1.29 (J=7 Hz, CH₃), 3.6(CH₂), 3.78 (J=7 Hz, NCH₂), 4.66 (OCH₂), 6.99 (ArH) and 7.05 (ArH) ppm.

Starting with the requisite 1-substituted-5-hydroxyoxindole andfollowing the procedures of Preparation B,5-methyl-3,6-dioxo-2,3,6,7-tetrahydrofuro[2,3-f]indole,5-phenyl-3.6-dioxo-2,3,6,7-tetrahydrofuro[2,3-f]indole,5-n-propyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole and5-i-propyl-3,6-dioxo-2,3,6,7-tetrahydro-furo[2,3-f]indole are prepared.

PREPARATION C ##STR127##1-Ethyl-2,3,6,11-tetrahydro-2,11-dioxo-[2]-benzoxepino[3,4-f]indole C1.1-ethyl-5-(2-carboxybenzyloxy)oxindole

To a solution of 2.24 g. (54.3 mmoles) of sodium hydroxide in 450 ml. ofmethanol was added 9.63 g. (54.3 mmoles) of 1-ethyl-5-hydroxyoxindoleand the resulting solution concentrated in vacuo to dryness at 65° C.The residual sodium salt was mixed with 10.7 g. (79.8 mmoles) ofphthalide and the mixture heated one hour at 185° C. An additional 4.0g. (29.9 mmoles) of phthalide was added and the heating continued at220° C. for 20 minutes. The reaction was cooled, the solids washed withdiethyl ether and the remaining solids partitioned between 1Nhydrochloric acid and diethyl ether. The organic phase was separated andextracted with a saturated sodium bicarbonate solution. The bicarbonatesolution was separated, acidified with 4N hydrochloric acid andextracted with diethyl ether. The ether layer was separated, dried overmagnesium sulfate and concentrated to give a solid. Recrystallizationfrom methanol gave 4.0 g. (24% yield) of the desired product, m.p. 180°-181° C.

Anal. Calcd. for C₁₈ H₁₇ O₄ N: C, 69.4; H, 5.5; N, 4.5. Found: C, 69.5;H, 5.5; N, 4.5.

C2. 1-ethyl-2,3,6,11-tetrahydro-2,11-dioxo-[2]benzoxepino[3,4-f]indole

To a suspension of 5.0 g. (16.1 mmoles) of1-ethyl-5-(2-carboxybenzyloxy)oxindole in 100 ml. of methylene chloridewas added 3.34 g. (16.1 mmoles) of phosphorous pentachloride and thereaction mixture allowed to stir 30 minutes at 25° C. The reactionmixture was cooled to --15° C. and 8.56 g. (64.4 mmoles) of aluminumchloride was added. The resulting mixture was allowed to stir at roomtemperature for 30 minutes and was then added to ice. The organic phasewas separated, dried over magnesium sulfate and concentrated to give thedesired product which was recrystallized from ethyl acetate-hexane, 2.3g (69% yield), m.p. 186.5°-188.5° C.

The NMR spectrum (CDCl₃) showed absorption at 1.24 (t, J=7 Hz, CH₃),3.45 (s, CH₂), 3.8 (q, J=7 Hz, NCH₂), 5.11 (s, OCH₂) and 6.8-8.0 (m,ArH) ppm.

Starting with the appropriate 5-hydroxyoxindole and using the procedureof Preparation C,1-methyl-2,3,6,11-tetrahydro-2,11-dioxo-[2]benzoxepino[3,4-f]-indole,1-n-propyl-2,3,6,11-tetrahydro-2,11-dioxo[2]-benzoxepino[3,4-f]indoleand1-i-propyl-2,3,6,11-tetrahydro-2,11-dioxo-[2]benzoxepino[3,4-f]indoleare prepared.

PREPARATION D ##STR128## Ethyl 1-ethyl-5-benzoyloxindole-3-carboxylateD1. 1-ethyl-5-benzoyloxindole

To a mixture of 26.18 g. (186 mmoles) of benzoyl chloride and 32.95 g.of aluminum chloride in 30 ml. of nitrobenzene was gradually added 10.0g. (62.1 mmoles) of 1-ethyloxindole. The reaction mixture was heated to100° C. for one hour, cooled and added to 2 l. of ice-water withstirring. The mixture was extracted with methylene chloride (5×200 ml.)and the extracts dried over magnesium sulfate and concentrated in vacuo.The nitrobenzene was distilled from the residue under high vacuum andthe residue treated with diethyl ether to induce crystallization. Theresulting solids were filtered and recrystallized from methylenechloride petroleum ether, 7.05 g. (42.8% yield), m.p. 134°-136° C.

The NMR (CDCl₃) spectrum showed absorption at 1.28 (t, J=7 Hz, CH₃),3.52 (s, CH₂), 3.79 (q, J=7 Hz, CH₂), 6.8 (d, J=8 Hz, ArH) and 7.6-8.0(m, ArH) ppm.

D2. ethyl 1-ethyl-5-benzoyloxindole-3-carboxylate

To a solution of 1.89 g. of sodium metal in 55 ml. of ethanol cooled to0° C. was added 9.96 ml. of diethyl carbonate followed by 6.5 g. (27.43mmoles) of 1-ethyl-5-benzoyloxindole. After heating for 2 hours at 65°C. on an oil bath, the reaction mixture was poured into a cold mixtureof 250 ml. 1N hydrochloric, 250 ml. of a saturated brine solution and200 ml. of methylene chloride. The organic phase was separated, driedand concentrated in vacuo. The excess diethylcarbonate was removed underhigh vacuum and the residue recrystallized from methylene chloride andcyclohexane, 2.1 g. 1st crop and 3.78 g. 2nd crop.

The NMR spectrum (CDCl₃) showed absorption at 1.29 (m, 2CH₃), 3.6-4.6(m, 2CH₂) and 6.8-8.3 (m, ArH) ppm.

PREPARATION E ##STR129## Ethyl 7-benzoyloxindole-3-carboxylate

To a slurry of 365 mg. of sodium hydride in 8 ml. of dimethylformamideat 0° C. was gradually added 1.0 g. (4.22 mmoles) of 7-benzoyloxindole,and the mixture allowed to stir for 10 minutes in an ice bath. Diethylcarbonate (1.53 g., 12.7 mmoles) was added and the reaction mixtureallowed to stir at ice bath temperatures for 3 hours. The mixture wasthen poured into 200 ml. of ice and water and the resulting precipitatefiltered, washed with water and vacuum dried, 940 mg. The crude productwas slurried in diethyl ether, filtered and the filtrate extracted with0.1N aqueous sodium hydroxide solution. The base layer was separated andacidified with hydrochloric acid. The resulting precipitate was filteredand dried, 109 mg., m.p. 134° C. (dec.).

The NMR spectrum (CDCl₃) showed absorption at 1.42 (t, J=7 Hz, CH₃),4.42 (q, J=7 Hz, CH₂), 6.8-8.3 (m, ArH) and 10.4 (bs, NH) ppm.

PREPARATION F ##STR130## 1-Methyl-7benzoyloxindole F1.1-methyl-7-benzoylindole

A mixture of 8.57 g. (38.8 mmoles) of 7-benzoylindole, 5.38 g. (42.7mmoles) of dimethyl sulfate and 5.12 g. of 85% potassium hydroxide in 40ml. of acetone was heated to reflux for 75 minutes. The mixture waspoured into 500 ml. of water and extracted with methylene chloride. Theorganic phase was separated, dried and concentrated. The residue waschromatographed on silica gel using methylene chloride-hexane as theeluant. The fractions containing the product were combined andconcentrated to dryness, 6.5 g.

The NMR spectrum (CDCl₃) showed absorption at 3.6 (s, CH₃), 6.52 (d, J=4Hz, vinyl H), 7.0 (d, J=4 Hz, vinyl H) and 7.1-8.0 (m, ArH) ppm.

F2. 1-methyl-7-benzoyloxindole

To a solution of 6.17 g. (26.25 mmoles) of 1-methyl-7-benzoylindole in62 ml. of methylene chloride was added 3.58 g. (26.25 mmoles) of 98%N-chlorosuccinimide and the mixture allowed to stir for 90 minutes. Anadditional 720 mg. of N-chlorosuccinimide was added and stirringcontinued for 2 hours. The reaction mixture was concentrated in vacuoand 52 ml. of acetic acid added. The mixture was heated to 80° C. and 27ml. of 85% phosphoric acid was added. The temperature was raised toreflux for 90 minutes and the reaction was cooled and poured into 200ml. of ice and water. The precipitate was filtered, dissolved inmethylene chloride and the solution dried with magnesium sulfate.Removal of the solvent gave a residue which was dissolved in 5% diethylether-methylene chloride and filtered through silica gel. The fractionswere collected, combined and concentrated to give 4.0 g. of the productas a viscous oil.

The NMR spectrum (CDCl₃) showed absorption at 2.99 (s, CH₃), 3.55 (s,CH₂) and 7.0-8.0 (m, ArH) ppm.

PREPARATION G ##STR131## 1-Ethyl-6-benzoyloxindole

G1. diethyl 2-nitro-4-benzoylphenylmalonate

To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole)of sodium metal with 200 ml. of ethanol, at 0° C. was added 32 g. (0.2mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of4-chloro-3-nitrobenzophenone. The mixture was allowed to stir at roomtemperature for 2 hours and was then poured into 400 ml. of ice cold 2Nhydrochloric acid and 300 ml. of methylene chloride. The organic layerwas separated, dried over magnesium sulfate and concentrated to an oil.The residual oil was induced to crystallize by trituration with hexanecontaining trace amounts of diisopropyl ether, 34.75 g., m.p. 68°-70° C.The sample was further purified by trituration with hothexane-diisopropyl ether, 30.84 g. (80% yield).

Anal. Calcd. for C₂₀ H₁₉ NO₇ : C, 62.3; H, 5.0; N, 3.6. Found: C, 62.3;H, 4.9; N, 3.6.

G2. 2-nitro-4-benzoylphenylacetic acid

A mixture of 14 g. (36.3 mmoles) of diethyl2-nitro-4-benzoylphenylmalonate, 300 ml. of 4N hydrochloric acid and 300ml. of dioxane was heated to reflux for 10 hours. The reaction mixturewas concentrated in vacuo and the crude product was triturated with hotmethylene chloride, 9.88 g. (95% yield), m.p. 168°-170° C.

Anal. Calcd. for C₁₅ H₁₁ NO₅ : C, 63.2; H, 3.9; N, 4.9. Found: C, 62.9;H, 4.0; N, 4.9.

G3. ethyl 2-nitro-4-benzoylphenylacetate

To a solution of 13.8 g. (48.4 mmoles) of 2-nitro-4-benzoylphenylaceticacid in 150 ml. of 1,2-dimethoxyethane at 15° C. was added 5.87 g. (58.1mmole) of triethylamine. After 5 minutes 5.75 g. (53.2 mmoles) ofethylchloroformate was added and the reaction mixture allowed to stir at10° C. for 15 minutes. Ethanol (15 ml.) was added and the reactionsubsequently was added to a mixture of diethyl ether and a saturatedbrine solution. The organic phase was separated, dried over magnesiumsulfate and concentrated to an oil, which was induced to crystallize,14.3 g. (94% yield), m.p. 61°-62° C.

Anal. Calcd. for C₁₇ H₁₅ NO₅ : C, 65.2; H, 4.8; N, 4.5. bound: C, 65.0;H, 4.8; N, 4.3.

G4. ethyl 2-amino-4-benzoylphenylacetate

To a solution of 14 g. (44.7 mmoles) of ethyl2-nitro-4-benzoylphenylacetate in 225 ml. of ethanol was added 15 g. ofwet Raney nickel and the mixture heated to reflux for 1.5 hours. Themixture was filtered and the filtrate concentrated to give a residualoil which was induced to crystallize by trituration with diethyl ether,7.9 g., m.p. 150°-152° C.

The NMR spectrum (CDCl₃) showed absorption at 1.24 (t, J=7 Hz, CH₃),3.61 (s, CH₂), 4.13 (q, J=7 Hz, CH₂) and 7.0-7.9 (m, ArH) ppm.

G5. 6-benzoyloxinole

A mixture of 5.0 g. (17.6 mmoles) of ethyl2-amino-4-benzoylphenylacetate and 999 mg. of p-toluene-sulfonic acid in300 ml. of toluene was heated to 110° C. for 5 minutes. The reaction wascooled and added to a mixture of methylene chloride and a saturatedsodium bicarbonate solution. The organic phase was separated, dried andconcentrated to a solid, 3.68 g. (88% yield), m.p. 206°-208° C.

The NMR spectrum (CDCl₃ +d₆ -DMSO) showed absorption at 3.52 (s, CH₂),7.1-7.9 (m, ArH) and 10.1 (bs, NH) ppm.

G6. 1-ethyl-6-benzoyloxindole

To a slurry of 1.28 g. (32 mmoles) of potassium hydride in 8 ml. ofdimethylformamide at 0° C. was added 1.77 g. (7.47 mmoles) of6-benzoyloxindole, followed after a few minutes by 1.2 g. (8 mmoles) ofdiethyl sulfate. After 30 minutes, the reaction was poured into amixture of methylene chloride and cold 1N hydrochloric acid. The organicphase was separated, dried and concentrated to dryness. The residue waschromatographed on silica gel using methylene chloridediethyl ether(5:1, v:v) as the eluant. The fractions containing the product werecombined and concentrated to dryness, 352 mg. (18% yield), m.p.120°-121° C.

Anal. Calcd. for C₁₇ H₁₅ NO₂ : C, 77.0; H, 5.7; N, 5.3. Found: C, 76.8;H, 5.7; N, 5.2.

Starting with 6-benzoyloxindole and the appropriate dialkyl sulfate andemploying the procedure of Preparation G6, 1-methyl-6-benzoyloxindole,1-n-propyl-6-benzoyloxindole and 1-i-propyl-6-benzoyloxindole areprepared.

PREPARATION H ##STR132## Ethyl1-ethyl-5-(2-thenoyl)oxindole-3-carboxylate H1.1-ethyl-5-(2-thenoyl)oxindole

To a mixture of 27.3 g. (19.9 mmoles) of 2-thenoyl chloride, 30 ml. ofnitrobenzene and 32.95 g. of aluminum chloride was gradually added 10 g.(62 mmoles) of 1-ethyloxindole, and the resulting reaction mixtureheated at 100° C. for 75 minutes. The reaction was cooled to roomtemperature and poured into 2 l. of ice and water. The product wasextracted with methylene chloride and the dried extract concentrated todryness, 11.05 g. The product was recrystallized from methylenechloride-hexane, 8.03 g. (47.7% yield)m, m.p. 158°-160° C.

The NMR spectrum (CDCl₃) showed absorption at 1.30 (t, J=7 Hz, CH₃),3.59 (s, CH₂), 3.81 (q, J=7 Hz, CH₂), 6.89 (d, J=8 Hz, ArH), 7.2 (m,ArH) and 7.5-8.0 (m, ArH) ppm.

H2. ethyl 1-ethyl-5-(2-thenoyl)oxindole-3-carboxylate

To sodium ethoxide, formed by adding 2 g. of sodium metal to 58 ml. ofethanol, at 0° C. was added 7.84 g. (28.9 mmoles) of1-ethyl-5-(2-thenoyl)oxindole followed by 10.24 g. (86.8 mmoles) ofdiethyl carbonate, and the reaction heated to 65° C. for 2 hours. Thereaction mixture was poured into a cold mixture of 250 ml. 1Nhydrochloric acid, 250 ml. of a saturated brine solution and 200 ml. ofmethylene chloride. The organic phase was separated, dried overmagnesium sulfate and concentrated in vacuo. The residue was trituratedwith diethyl ether and filtered. The filtrate was subsequentlyconcentrated to dryness under vacuum to give the desired product, 5.4 g.(54.4% yield).

The NMR spectrum (CDCl₃) showed absorption at 1.29 (m, 2CH₃), 3.5-4.6(m, 2CH₂) and 6.5-8.4 (m, ArH) ppm.

PREPARATlON I ##STR133## Ethyl 7-acetyoxindole-3-carboxylate I1.7-acetyloxindoline

To a solution of 47.35 g. (0.5 mole) of boron tribromide in 300 ml. oftoluene at 0° C. was added dropwise a solution of 50 g. (0.42 mole) ofindoline and 22.39 g. (0.546 mole) of acetonitrile in 200 ml. oftoluene. After stirring for 10 minutes 67.2 g. (0.5 mole) of aluminumchloride was added in portions. The resulting reaction mixture washeated to reflux for 66 hours, cooled to 5° C. and treated with 80 ml.of water and 330 ml. of 2-N hydrochloric acid. The resulting mixture washeated to reflux for 2.5 hours, cooled and filtered. The filtrate wasset aside and the solids suspended in 500 ml. of water and treated with2N sodium hydroxide solution until basic. The basic mixture wasextracted (2×200 ml.) with methylene chloride and the organic phaseseparated, dried and concentrated to a solid, 17.2 g. The filtrate whichwas set aside was made basic with 4N aqueous sodium hydroxide andextracted with methylene chloride. The organic phase was separated,dried and concentrated to a solid, 21.8 g. The combined solids wererecrystallized from hexane, 30 g., m.p. 83°-85° C.

The NMR spectrum (CDCl3) showed absorption at 2.53 (s, CH₃), 3.05 (bt,J=8 Hz, CH₂), 3.75 (bt, J=8 Hz, CH₂), 6.5 (dd, J=8 Hz, ArH), 7.13 (bd,J=8 Hz, ArH), 7.15 (b, NH) and 7.4 (bd, J=8 Hz, ArH) ppm.

I2. 7-acetylindole

To 30 g. (0.186 mole) of 7-acetylindoline in 415 ml. of methylenechloride was added 48.5 g. (0.56 mole) of manganese dioxide and themixture refluxed through a soxhlet filled with 4A molecular sieves for22 hours. The mixture was cooled and an additional 48.5 g. of manganesedioxide was added. Fresh molecular sieves were added and the refluxingcontinued for 5 hours. The same amount of manganese dioxide andmolecular sieves were added again and the refluxing was continued forone hour. The mixture was filtered and the filtrate concentrated todryness. The residue was triturated with hexane and filtered, 22.57 g.(76% yield), m.p. 65°-66° C.

The NMR spectrum (CDCl₃) showed absorption at 2.69 (s, CH₃), 6.52 (dd,J=3 and 3 Hz, vinyl H), 7.12 (d, J=8 Hz, ArH), 7.25 (d, J=3 Hz, vinyl H)and 7.78 (m, ArH) ppm.

I3. 7-acetyloxindole

To a solution of 12.57 g. (79 mmoles) of 7-acetylindole in 187 ml. ofmethylene chloride was added 11.07 g. (82.9 mmoles) ofN-chlorosuccinimide and the reaction allowed to stir at room temperaturefor 2 hours. The solvent was removed in vacuo and the residue treatedwith 155 ml. of acetic acid and heated to 80° C. Phosphoric acid (80ml.) was added and the reaction mixture heated to reflux for 9 hours.The mixture was cooled, the acetic acid removed under vacuum and theresidue poured into 500 ml. of ice and water. The product was extractedwith methylene chloride, 11.91 g. (65% yield), 174°-175° C.

The NMR spectrum (CDCl₃) showed absorption at 2.6 (s, CH₃), 3.49 (s,CH₂), 7.01 (dd, J=8 and 8 Hz, ArH), 7.25 (d, J=8 Hz, ArH) and 7.66 (d,J=8 Hz, ArH) ppm.

I4. ethyl 7-acetyloxindole-3-carboxylate

To a slurry of 1.85 g. of sodium hydride in 49 ml. of dimethylformamideat 0° C. was added 4.5 g. (0.0257 mole) of 7-acetyloxindole. When theevolution of hydrogen ceased 9.1 g. (0.0771 mole) of diethyl carbonatewas added and the mixture allowed to stir in the cold for 5 hours. Thereaction mixture was poured into 500 ml. of ice and water and 40 ml. of4N hydrochloric acid. The resulting precipitate was filtered and driedin vacuo, 5.38 g. The product was recrystallized from methylenechloride-diisopropyl ether, 2.27 g. (35.7% yield), m.p. 186°-190° C.

The NMR spectrum (d₆ -DMSO) showed absorption at 1.32 (t, J=7 Hz, CH₃),2.61 (s, CH₃), 4.25 (q, J=7 Hz, CH₂), 7.15 (dd, J=7.5 and 7.5 Hz, ArH),7.6 (d, J=7.5 Hz, ArH), 8.0 (d, J=7.5 Hz, ArH) and 11.1 (bs, 1H) ppm.

In a similar manner, by starting with the appropriate indoline andemploying the procedures of Preparation I, the following7-acetyloxindoles are prepared: ethyl1-methyl-7-acetyloxindole-3-carboxylate, ethyl1-ethyl-7-acetyloxindole-3-carboxylate, ethyl1-n-propyl-7-acetyloxindole-3-carboxylate and ethyl1-i-propyloxindole-3-carboxylate.

PREPARATION J ##STR134## Ethyl1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylateJ1. 1-ethyl-5-acetyloxindole

To a mixture of 29.25 g. (0.373 mole) of acetyl chloride and 65.9 g. ofaluminum chloride in 60 ml. of nitrobenzene was added gradually 20.0(0.124 mole) of 1-ethyloxindole. The reaction warmed to about 45° C.with an evolution of gas. After stirring for one hour the reaction washeated to 100° C. for one hour and allowed to stir at room temperatureover night. The reaction mixture was poured into 2 l. of ice withstirring. After 30 minutes the product was filtered, air dried anddissolved in 200 ml. of methylene chloride. The solution was dried overmagnesium sulfate and concentrated to dryness. The residue wasrecrystallized from toluene, 14.44 g. (57.3% yield), m.p. 141°-145° C.

The NMR spectrum (CDCl₃) showed absorption at 1.29 (t, J=7 Hz, CH₃),2.56 (s, CH₃), 3.52 (s, CH₂), 3.82 (q, J=7 Hz, CH₂), 6.85 (d, J=8 Hz,ArH) and 7.9 (m, ArH) ppm.

J2. 1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole

A mixture of 10.0 g. (49.26 mmoles) of 1-ethyl-5-acetyloxindole, 27.4ml. of ethylene glycol and a trace of p-toluene sulfonic acid in 300 ml.of benzene was refluxed through a soxhlet filled with 4A sieves for 13hours. The reaction was cooled to room temperature and poured into asaturated sodium bicarbonate solution. The organic layer was separated,dried over magnesium sulfate and concentrated to dryness. The residuewas recrystallized from hexane-methylene chloride, 10.79 g. (90% yield),m.p. 95-98%.

The NMR spectrum (CDCl₃) showed absorption at 1.22 (t, J=7 Hz, CH₃),1.65 (s, CH₃), 3.48 (s, CH₂), 3.6-4.2 (m, (CH₂ O)₂), 6.73 (d, J=8 Hz,ArH) and 7.35 (m, ArH) ppm.

J3. ethyl 1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3carboxylate

Sodium (1.39 g.) was reacted with 40 ml. of ethanol and cooled to 0° C.in an ice bath. To the cold solution was added 7.3 ml. (60.7 mmoles) ofdiethyl carbonate followed by 5.0 g. (20.24 mmoles) of1-acetyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole and theresulting reaction mixture heated to 65° C. for 2 hours. The reactionwas cooled to room temperature and added to a mixture of ice 200 ml.water and 200 ml. methylene chloride containing 3.45 ml. of acetic acid.The organic phase was separated, washed with a saturated sodiumbicarbonate solution and dried over magnesium sulfate. Removal of thesolvent gave 4.99 g. (70% yield) of product m.p. 73°-75° C.

The NMR spectrum (CDCl₃) showed absorption at 1.28 (t, J=7 Hz, CH₃),1.65 (s, CH₃), 3.5-4.6 (m, 4CH₂, CH), 6.8 (d, J=8 Hz, ArH) and 7.1-7.6(m, ArH) ppm.

By starting with the requisite oxindole and employing the procedure ofPreparation J, the following intermediates are prepared:

ethyl 5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate,ethyl1-methyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate,ethyl1-n-propy-l-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylateand ethyl1-i-propyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate.

I claim:
 1. Compounds of the formula ##STR135## and the pharmaceuticallyacceptable base salts thereof, wherein Z is selected from the groupconsisting of oxygen and methylene; R₁ is selected from the groupconsisting of phenyl and alkyl containing from one to three carbonatoms; and R₂ is selected from the group consisting of phenyl,fluorophenyl, difluorophenyl, pyridyl, trifluoromethylphenyl,nitrophenyl, 2-thiazolyl and 5-methyl-2-thiazolyl.
 2. A compound ofclaim 1, wherein Z is methylene and R₁ is alkyl containing one to threecarbon atoms.
 3. The compound of claim 2, wherein R₁ is ethyl and R₂ is4-fluorophenyl.
 4. The compound of claim 2, wherein R₁ is ethyl and R₂is 2,4-difluorophenyl.
 5. The compound of claim 2, wherein R₁ is ethyland R₂ is 3-trifluoromethylphenyl.
 6. Compounds of the formula##STR136## and the pharmaceutically acceptable base salts thereof,wherein R₁ is selected from the group consisting of phenyl and alkylcontaining one to three carbon atoms; and R₃ is selected from the groupconsisting of phenyl, fluorophenyl, difluorophenyl, pyridyl, 2-thiazolyland 5-methyl-2-thiazolyl.
 7. A compound of claim 6, wherein R₁ is alkylcontaining one to three carbon atoms.
 8. The compound of claim 7,wherein R₁ is ethyl and R₃ is 2,4-difluorophenyl.
 9. A method oftreating an inflammatory disease in a mammalian subject, which comprisesadministering to said subject an inflammatory disease treating amount ofa compound according to claim 1 or
 6. 10. A pharmaceutical composition,with comprises a pharmaceutically-acceptable carrier and an inflammatorydisease treating amount of a compound according to claim 1 or 6, andwherein the weight-ratio of the pharmaceutically-acceptable carrier tosaid compound is in the range of from 1:4 to 20:1.